A5031519165- RNA and protein synthesis mechanisms
- Enzyme Catalysis and Immobilization
- Biochemical and Molecular Research
- Melanoma and MAPK Pathways
- Enzyme Structure and Function
- Microbial Natural Products and Biosynthesis
- Protein Kinase Regulation and GTPase Signaling
- Cancer-related Molecular Pathways
- Cancer-related gene regulation
- Advanced Biosensing Techniques and Applications
- Antimicrobial Resistance in Staphylococcus
- Chemistry and Chemical Engineering
- Bacterial Genetics and Biotechnology
- Peptidase Inhibition and Analysis
- PI3K/AKT/mTOR signaling in cancer
- Protease and Inhibitor Mechanisms
- Wnt/β-catenin signaling in development and cancer
- RNA modifications and cancer
- Asymmetric Hydrogenation and Catalysis
- Cytokine Signaling Pathways and Interactions
- HIV/AIDS drug development and treatment
- Radical Photochemical Reactions
- Chemical Synthesis and Analysis
- Fungal and yeast genetics research
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
GlaxoSmithKline (United Kingdom)
2007-2023
GlaxoSmithKline (Netherlands)
2022
Age UK
2017-2021
GlaxoSmithKline (Brazil)
2020
Institute of Medicinal Plant Development
2020
GlaxoSmithKline (India)
2019-2020
University of St Andrews
2020
New Frontier
2000-2002
South College
2002
Molecular Discovery (United Kingdom)
2001
Abstract Biocatalysis over the past few years has matured into an essential tool for modern, cost effective and sustainable pharmaceutical manufacturing. While some reaction classes are well established, may even be option of first intent, other more recently discovered enzyme being rapidly developed both in academia industry. Notwithstanding this, there further promising enzymes that require investment investigation to allow their future industrial use. We here outline GSK's perspective on...
Macrocyclic polyketides exhibit an impressive range of medically useful activities, and there is great interest in manipulating the genes that govern their synthesis. The 6-deoxyerythronolide B synthase (DEBS) Saccharopolyspora erythraea , which synthesizes aglycone core antibiotic erythromycin A, has been modified by repositioning a chain-terminating cyclase domain to carboxyl-terminus DEBS1, multienzyme catalyzes first two rounds polyketide chain extension. resulting mutant markedly...
Abstract Chiral secondary and tertiary amines are ubiquitous in pharmaceutical, fine, specialty chemicals, but their synthesis typically suffers from significant sustainability selectivity challenges. Biocatalytic alternatives, such as enzyme‐catalyzed reductive amination, offer several advantages over traditional chemistry, industrial applicability has not yet been demonstrated. Herein, we report the use of cell lysates expressing imine reductases operating at 1:1 stoichiometry for a...
Article29 January 2021Open Access Transparent process Development of a small molecule that corrects misfolding and increases secretion Z α1-antitrypsin David A Lomas Corresponding Author [email protected] orcid.org/0000-0003-2339-6979 UCL Respiratory, Rayne Institute, University College London, UK Search for more papers by this author James Irving orcid.org/0000-0003-3204-6356 Christopher Arico-Muendel GlaxoSmithKline, Cambridge, MA, USA Svetlana Belyanskaya Andrew Brewster Stevenage, Murray...
Potent nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase have been derived from a file compound high throughput screening hit. Optimized compounds show excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics. Compound 11 demonstrated in vivo efficacy an S. rat abscess infection model.
A kinase-focused screening set of fragments has been assembled and proved successful for the discovery ligand-efficient hits against many targets. Here we present some our general conclusions from this exercise. Notably, first profiling results literature that have previously used as starting points optimization individual kinases. We consider importance format extent to which selectivity is helpful in selecting progression. Results are also outlined targeting DFG-out conformation atypical...
Towards scalable ATP recycling: a newly identified PPK2-III biocatalyst unlocked fully<italic>in vitro</italic>multigram-scale aldehyde synthesis employing carboxylic acid reductase.
Glycogen synthase kinase 3 (GSK‐3) has previously been shown to play an important role in the regulation of apoptosis. However, nature GSK‐3 effector pathways that are relevant neuroprotection remains poorly defined. Here, we have compared resulting from modulation activity PC12 cells using either selective small molecule ATP‐competitive inhibitors (SB‐216763 and SB‐415286), or adenovirus overexpressing requently earranged dvanced ‐cell lymphomas 1 (FRAT1), a protein proposed as negative...
This paper describes the design and characterization of novel inhibitors IleRS, whose binding affinity approaches tightest reported for noncovalent inhibition. Compounds were designed from a model natural product pseudomonic acid-A (PS-A) together with detailed understanding reaction cycle IleRS mode intermediate IleAMP. The interactions compounds characterized by inhibition aminoacylation tRNA or PP(i)/ATP exchange at supersaturating substrate concentration transient kinetics calorimetry...
Abstract Polyphosphate kinases (PPKs) have emerged as valuable candidates to address the unmet need for scalable recycling of common enzyme cofactor adenosine‐5’‐triphosphate (ATP) because they use cheap, freely available and stable polyphosphate (polyP) salts phosphate donor. The aim this review is not only present recent efforts in characterisation PPKs but also provide an overview challenges associated with their implementation chemical manufacturing. In assessing current status...
The interactions of isoleucyl-tRNA synthetase (IleRS, <i>E</i>) from <i>Staphylococcus aureus</i> with both intermediate analogues and pseudomonic acid (PS-A) have been investigated using transient steady-state techniques. Non-hydrolyzable isoleucyl-AMP (I) were simple competitive inhibitors (Ile-ol-AMP, <i>K</i> <sub>i</sub> = 50 nm Ile-NHSO<sub>2</sub>-AMP, 1 nm;). PS-A (J) inhibits IleRS via a slow-tight binding mechanism where <i>E</i>·<i>J</i> (<i>K</i> <sub>j</sub> ∼2 nm), undergoes an...
This paper describes, for the first time, a true ultra-high throughput screen (uHTS) based upon fluorescence anisotropy and performed entirely in 1536-well assay plates. The is binding displacement of BODIPY-FL-labeled antibiotic to specific site on 70S ribosomes from Escherichia coli (Kd approximately 15 nM). was at uHTS rates (i.e., >100,000 wells/24 h) using commercially available equipment. In order examine reproducibility detection test compound effects, assays were duplicate. Both...